Evolutionarily conserved regulation of hypocretin neuron specification by Lhx9
Loss of neurons that express the neuropeptide hypocretin (Hcrt) has been implicated in narcolepsy, a debilitating disorder characterized by excessive daytime sleepiness and cataplexy. Cell replacement therapy, using Hcrt-expressing neurons generated in vitro, is a potentially useful therapeutic approach, but factors sufficient to specify Hcrt neurons are unknown. Using zebrafish as a high-throughput system to screen for factors that can specify Hcrt neurons in vivo, we identified the LIM homeobox transcription factor Lhx9 as necessary and sufficient to specify Hcrt neurons. We found that Lhx9 can directly induce hcrt expression and we identified two potential Lhx9 binding sites in the zebrafish hcrt promoter. Akin to its function in zebrafish, we found that Lhx9 is sufficient to specify Hcrt-expressing neurons in the developing mouse hypothalamus. Our results elucidate an evolutionarily conserved role for Lhx9 in Hcrt neuron specification that improves our understanding of Hcrt neuron development.
© 2015 The Company of Biologists Ltd. Received September 3, 2014; accepted January 15, 2015. Posted online before print February 27, 2015. We thank Farhad Imam for assistance with microarray data analysis, Anthony Kirilushna for EMSA assistance and Daniel Lee for comments on the manuscript. This work was supported by grants from the National Institutes of Health [F31NS77844 to J.L.; 1R21NS071598, 5K99NS083713 to F.T.M.; R01HL109525, R21NS071598 to A.F.S.; R00NS060996, R01NS070911, R01DA031367 to D.A.P.], the American Cancer Society [to J.A.G. and I.G.W.], the Jane Coffin Childs Memorial Fund for Medical Research [to F.T.M.], the RIKEN Brain Institute [to T.S.], the Mallinckrodt Foundation, the Rita Allen Foundation, and the Brain and Behavior Research Foundation [to D.A.P.]. Deposited in PMC for release after 12 months.
Published - Development-2015-Liu-1113-24.pdf